Lewy body dementia, which includes dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD), is collectively the second most common neurodegenerative dementia and is pathologically characterized by -synuclein positive cytoplasmic inclusions, with varying amounts of A and tau aggregates in addition to synaptic loss. Clinical hallmarks include fluctuating and deteriorating cognition, hallucinations and parkinsonism. A dysfunctional ubiquitin proteasome system (UPS) may be a mediating factor of disease progression and of the development of -synuclein aggregates. In the present study, protein expression of some key component subunits of the UPS and two of the three main proteolytic-like (chymotrypsin- and PGPH-) activities have been determined in the frontal cortex (Brodmann, BA9), the parietal cortex (BA40) and the anterior cingulate gyrus (BA24) of DLB, PDD, Alzheimer's disease (AD) and matched controls. Clinical and pathological data were available for the cases studied, with regard to the duration of dementia and parkinsonism, the Mini-Mental State Examination (MMSE) score, the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) plaque, the Braak stage and the -synuclein score. We hypothesised that cognitive decline and noncognitive symptoms were associated with the proteasome impairment as a consequence of synaptic dysfunction and increased protein aggregation in LBD and AD. To address the link between proteasome impairment, AD and LBD pathology, cognition decline and noncognitive symptoms, and the synaptic dysfunction, alteration of the proteasome components and activities have been investigated to identify clinical-pathological correlations. Our aim was to investigate possible relationships between a) decreased level of proteasome components and semi-quantitative scores of AD and LBD pathology in the selected brain areas, b) proteasome dysfunction and the cognition function and noncognitive symptoms in LBD and AD and c) reduction of proteasome components and synaptic dysfunction. Due to the importance of the protein degradation pathways in the development of Lewy bodies and the evidence from our studies indicative of proteasome dysfunction, the lysosomal pathway was also examined. Two lysosomal markers were chosen for investigation: cathepsin D and lysosomal-associated membrane protein 1 (LAMP1) and the same clinico-pathological correlations were applied for the lysosomal markers. The major finding of this project was the reduction in the RPT6 ATPase 19S regulatory subunit in DLB and AD; this reduction was associated with the decrease in proteasome activity and synaptic markers (PSD-95, ZnT3, synaptophysin and beta-IIItubulin). Both reductions of RPT6 and decreases in proteasome activity predicted cognitive decline, depression and severity of amyloid-beta and tau pathology in the examined brain regions.
|Date of Award
|Tibor Hortobagyi (Supervisor) & Paul Francis (Supervisor)